The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory ...The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory molecules,which lead to repair failure.Accordingly,blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination.In the central nervous system,oligodendrocytes form the myelin sheath.We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation.Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin’s pro-proliferation function.Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation,as well as PI3K signaling pathways that are needed in the mid-late stages.When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination,it enhanced myelin regeneration and promoted motor function recovery.These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.展开更多
Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarizatio...Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarization in NAFLD remains unclear.Herein,we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7(17β-HSD7)expression in hepatic macrophages concomitantly with elevated M1 polarization.Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet(HFD)for 6 weeks revealed that lipid metabolism pathways were notably changed.Furthermore,17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis,insulin resistance and liver injury.Mechanistically,17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content,thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines.In addition,to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD,fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity.Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production,and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages.In conclusion,our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.展开更多
基金supported by the National Nature Science Foundation of China,Nos.81371338(to HF)and 82071369(PPY)。
文摘The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory molecules,which lead to repair failure.Accordingly,blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination.In the central nervous system,oligodendrocytes form the myelin sheath.We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation.Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin’s pro-proliferation function.Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation,as well as PI3K signaling pathways that are needed in the mid-late stages.When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination,it enhanced myelin regeneration and promoted motor function recovery.These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.
基金supported by the National Nature Science Foundation of China(Nos.82173872 and 81872663)。
文摘Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarization in NAFLD remains unclear.Herein,we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7(17β-HSD7)expression in hepatic macrophages concomitantly with elevated M1 polarization.Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet(HFD)for 6 weeks revealed that lipid metabolism pathways were notably changed.Furthermore,17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis,insulin resistance and liver injury.Mechanistically,17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content,thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines.In addition,to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD,fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity.Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production,and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages.In conclusion,our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.
